{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:26:42Z","timestamp":1792790802570,"version":"4.5.0"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T00:00:00Z","timestamp":1616025600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T00:00:00Z","timestamp":1616025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Norwegian Instotute of Public Health","id":[{"id":"https:\/\/ror.org\/046nvst19","id-type":"ROR","asserted-by":"crossref"}]},{"name":"EBTC"},{"name":"Safer Medicines Trust","id":[{"id":"https:\/\/ror.org\/029v85503","id-type":"ROR","asserted-by":"crossref"}]},{"name":"US Food and Drug Administration","id":[{"id":"https:\/\/ror.org\/034xvzb47","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Drug-induced liver injury (DILI) causes one in three market withdrawals due to adverse drug reactions, causing preventable human suffering and massive financial loss. We applied evidence-based methods to investigate the role of preclinical studies in predicting human DILI using two anti-diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market). Evidence Stream 1: A systematic literature review of in vivo studies on rosiglitazone or troglitazone\u00a0was conducted (PROSPERO registration CRD42018112353). Evidence Stream 2: in vitro data on troglitazone and rosiglitazone were retrieved from the US EPA ToxCast database. Evidence Stream 3: troglitazone- and rosiglitazone-related DILI cases were retrieved from WHO Vigibase. All three evidence stream analyses were conducted according to evidence-based methodologies and performed according to pre-registered protocols. Evidence Stream 1: 9288 references were identified, with 42 studies included in analysis. No reported biomarker for either drug indicated a strong hazard signal in either preclinical animal or human studies. All included studies had substantial limitations, resulting in \u201clow\u201d or \u201cvery low\u201d certainty in findings. Evidence Stream 2: Troglitazone was active in twice as many in vitro assays (129) as rosiglitazone (60), indicating a strong signal for more off-target effects. Evidence Stream 3: We observed a fivefold difference in both all adverse events and liver-related adverse events reported, and an eightfold difference in fatalities for troglitazone, compared to rosiglitazone. In summary,\u00a0published animal and human trials failed to predict troglitazone\u2019s potential to cause severe liver injury in a wider patient population, while in vitro data showed marked differences in the two drugs\u2019 off-target activities, offering a new paradigm for reducing drug attrition in late development and in the market. This investigation concludes that\u00a0death and disability due to adverse drug reactions may be prevented if mechanistic information is deployed at early stages of drug development by pharmaceutical companies and is considered by regulators as a part of regulatory submissions.<\/jats:p>","DOI":"10.1038\/s41598-021-85708-2","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T12:47:41Z","timestamp":1616071661000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Performance of preclinical models in predicting drug-induced liver injury in humans: a systematic review"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7686-9947","authenticated-orcid":false,"given":"Hubert","family":"Dirven","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunn E.","family":"Vist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sricharan","family":"Bandhakavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyotsna","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seneca E.","family":"Fitch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pandora","family":"Pound","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Ram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6200-5649","authenticated-orcid":false,"given":"Breanne","family":"Kincaid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8212-7632","authenticated-orcid":false,"given":"Cathalijn H. C.","family":"Leenaars","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3991-0015","authenticated-orcid":false,"given":"Robert A.","family":"Wright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8378-0430","authenticated-orcid":false,"given":"Katya","family":"Tsaioun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"key":"85708_CR1","unstructured":"US Food and Drug Administration, \u201cPreventable Adverse Drug Reactions: A Focus on Drug Interactions. ADRs: Prevalence and incidence,\u201d https:\/\/www.fda.gov\/drugs\/drug-interactions-labeling\/preventable-adverse-drug-reactions-focus-drug-interactions (Accessed 24 Mar 2020)."},{"issue":"7456","key":"85708_CR2","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1136\/bmj.329.7456.15","volume":"329","author":"M Pirmohamed","year":"2004","unstructured":"Pirmohamed, M. et al. Adverse drug reactions as cause of admission to hospital: Prospective analysis of 18,820 patients. Br. Med. J. 329(7456), 15\u201319 (2004).","journal-title":"Br. Med. J."},{"issue":"5","key":"85708_CR3","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s40264-015-0281-0","volume":"38","author":"JC Bouvy","year":"2015","unstructured":"Bouvy, J. C., De Bruin, M. L. & Koopmanschap, M. A. Epidemiology of adverse drug reactions in Europe: a review of recent observational studies. Drug Saf. 38(5), 437\u2013453 (2015).","journal-title":"Drug Saf."},{"issue":"6","key":"85708_CR4","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1517\/17425250902932915","volume":"5","author":"JK Gwathmey","year":"2009","unstructured":"Gwathmey, J. K., Tsaioun, K. & Hajjar, R. J. Cardionomics: a new integrative approach for screening cardiotoxicity of drug candidates. Expert Opin. Drug Metab. Toxicol. 5(6), 647\u2013660 (2009).","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"85708_CR5","unstructured":"Elliott, R., Camacho, E., Campbell, F., Jankovic, D., St James, M. M., Kaltenthaler, E., & Faria, R. Prevalence and economic burden of medication errors in the NHS in England: rapid evidence synthesis and economic analysis of the prevalence and burden of medication error in the UK www.eepru.org.uk\/wp-content\/uploads\/2020\/03\/medication-error-report-edited-27032020.pdf (Accessed 27 Mar 2020), (2018)."},{"key":"85708_CR6","unstructured":"Mullin, R. Tufts study finds big rise in cost of drug development. Chem. Eng. News http:\/\/www.cen.acs.org\/articles\/92\/web\/2014\/11\/Tufts-Study-Finds-Big-Rise.hl (Accessed 24 Mar 2020), (2014)."},{"issue":"9","key":"85708_CR7","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1001\/jama.2020.1166","volume":"323","author":"OJ Wouters","year":"2020","unstructured":"Wouters, O. J., McKee, M. & Luyten, J. Estimated research and development invesent needed to bring a new medicine to market, 2009\u20132018. JAMA 323(9), 844 (2020).","journal-title":"JAMA"},{"key":"85708_CR8","unstructured":"Thomas, D. W., et al. Clinical development success rates 2006\u20132015. https:\/\/www.bio.org\/sites\/default\/files\/legacy\/bioorg\/docs\/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf (Accessed 27 Mar 2020)."},{"issue":"12","key":"85708_CR9","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/nrd.2016.184","volume":"15","author":"RK Harrison","year":"2016","unstructured":"Harrison, R. K. Phase II and phase III failures: 2013\u20132015. Nat. Rev. Drug Discov. 15(12), 817\u2013818 (2016).","journal-title":"Nat. Rev. Drug Discov."},{"issue":"10","key":"85708_CR10","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/nrm2236","volume":"8","author":"F Pampaloni","year":"2007","unstructured":"Pampaloni, F., Reynaud, E. G. & Stelzer, E. H. K. The third dimension bridges the gap between cell culture and live tissue. Nat. Rev. Mol. Cell Biol. 8(10), 839\u2013845 (2007).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"1","key":"85708_CR11","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1002\/jcp.24683","volume":"230","author":"M Ravi","year":"2015","unstructured":"Ravi, M., Paramesh, V., Kaviya, S. R., Anuradha, E. & Solomon, F. D. P. 3D cell culture systems: advantages and applications. J. Cell. Physiol. 230(1), 16\u201326 (2015).","journal-title":"J. Cell. Physiol."},{"key":"85708_CR12","unstructured":"BioIndustry Association and Medicines Discovery Catapult, State of the Discovery Nation 2018 and the role of the Medicines Discovery Catapult, http:\/\/www.md.catapult.org.uk\/FlipBuilder\/mobile\/index.hl (Accessed 24 Mar 20)), (2018)."},{"issue":"1","key":"85708_CR13","doi-asserted-by":"publisher","first-page":"915","DOI":"10.2165\/11310890-000000000-00000","volume":"23","author":"H Geerts","year":"2009","unstructured":"Geerts, H. Of mice and men. Bridging the translational disconnect in CNS drug discovery. CNS Drugs 23(1), 915\u2013926 (2009).","journal-title":"CNS Drugs"},{"key":"85708_CR14","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/507423a","volume":"507","author":"S Perrin","year":"2014","unstructured":"Perrin, S. Preclinical research: make mouse studies work. Nature 507, 423\u2013425 (2014).","journal-title":"Nature"},{"issue":"1","key":"85708_CR15","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.theriogenology.2007.09.030","volume":"69","author":"RJ Wall","year":"2008","unstructured":"Wall, R. J. & Shani, M. Are animal models as good as we think?. Theriogenology 69(1), 2\u20139 (2008).","journal-title":"Theriogenology"},{"issue":"7","key":"85708_CR16","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nrd4609","volume":"14","author":"MJ Waring","year":"2015","unstructured":"Waring, M. J. et al. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat. Rev. Drug Discov. 14(7), 475\u2013486 (2015).","journal-title":"Nat. Rev. Drug Discov."},{"issue":"12","key":"85708_CR17","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1001\/jamainternmed.2016.6008","volume":"176","author":"TJ Hwang","year":"2016","unstructured":"Hwang, T. J. et al. Failure of investigational drugs in late-stage clinical development and publication of trial results. JAMA Intern. Med. 176(12), 1826 (2016).","journal-title":"JAMA Intern. Med."},{"key":"85708_CR18","unstructured":"Alliance for Human Relevant Science, Accelerating the growth of human relevant life sciences in the United Kingdom. A white paper by the alliance for human relevant science, www.humanrelevantscience.org\/wp-content\/uploads\/Accelerating-the-Growth-of-Human-Relevant-Sciences-in-the-UK_2020-final.pdf (Accessed 27 Mar 2020), (2020)."},{"key":"85708_CR19","unstructured":"Innovate UK, A non-animal technologies roadmap for the UK: advancing predictive biology, https:\/\/assets.publishing.service.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/474558\/Roadmap_NonAnimalTech_final_09Nov2015.pdf (Accessed 3 Mar 2020), (2015)."},{"issue":"12","key":"85708_CR20","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1177\/0141076818812783","volume":"111","author":"K Archibald","year":"2018","unstructured":"Archibald, K., Tsaioun, K., Kenna, J. G. & Pound, P. Better science for safer medicines: the human imperative. J. R. Soc. Med. 111(12), 433\u2013438 (2018).","journal-title":"J. R. Soc. Med."},{"key":"85708_CR21","doi-asserted-by":"publisher","first-page":"104662","DOI":"10.1016\/j.yrtph.2020.104662","volume":"114","author":"AM Avila","year":"2020","unstructured":"Avila, A. M. et al. An FDA\/CDER perspective on nonclinical testing strategies: classical toxicology approaches and new approach methodologies (NAMs). Regul. Toxicol. Pharmacol. 114, 104662 (2020).","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"85708_CR22","unstructured":"US Environmental Protection Agency, \u201cToxicity forecasting. Advancing the next generation of chemical evaluation,\u201d www.epa.gov\/chemical-research\/toxicity-forecasting (Accessed Mar 24 2020), (2019)."},{"issue":"3","key":"85708_CR23","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1056\/NEJMra1816149","volume":"381","author":"JH Hoofnagle","year":"2019","unstructured":"Hoofnagle, J. H. & Bj\u00f6rnsson, E. S. Drug-induced liver injury: types and phenotypes. N. Engl. J. Med. 381(3), 264\u2013273 (2019).","journal-title":"N. Engl. J. Med."},{"issue":"6","key":"85708_CR24","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1038\/clpt.2011.63","volume":"89","author":"PB Watkins","year":"2011","unstructured":"Watkins, P. B. Drug safety sciences and the bottleneck in drug development. Clin. Pharmacol. Ther. 89(6), 788\u2013790 (2011).","journal-title":"Clin. Pharmacol. Ther."},{"issue":"1","key":"85708_CR25","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1006\/rtph.2000.1399","volume":"32","author":"H Olson","year":"2000","unstructured":"Olson, H. et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 32(1), 56\u201367 (2000).","journal-title":"Regul. Toxicol. Pharmacol."},{"issue":"7","key":"85708_CR26","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.1007\/s00204-017-1980-3","volume":"91","author":"S Hoffmann","year":"2017","unstructured":"Hoffmann, S. et al. A primer on systematic reviews in toxicology. Arch. Toxicol. 91(7), 2551\u20132575 (2017).","journal-title":"Arch. Toxicol."},{"key":"85708_CR27","unstructured":"Tsaioun, K. et al. Systematic reviews of the hepatotoxic effects of specified compounds\/drugs as observed in humans and experimental animals (rats, mice, dogs and non-human primates). PROSPERO 2018 CRD42018112353. Available from https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?ID=CRD42018112353."},{"key":"85708_CR28","unstructured":"Scheen, A. J. Thiazolidinediones and liver toxicity. Diabetes Metab. 27(3), 305\u2013313 (2001). PMID: 11431595."},{"key":"85708_CR29","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1046\/j.1463-1326.2001.00159.x","volume":"3","author":"WL Isley","year":"2000","unstructured":"Isley, W. L. & Oki, J. C. Hepatotoxicity of thiazolidinediones. Diabetes Obes. Metab. 3, 389\u2013392 (2000).","journal-title":"Diabetes Obes. Metab."},{"issue":"4","key":"85708_CR30","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1016\/j.drudis.2016.02.015","volume":"21","author":"M Chen","year":"2016","unstructured":"Chen, M. et al. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov. Today 21(4), 648\u2013653 (2016).","journal-title":"Drug Discov. Today"},{"issue":"3","key":"85708_CR31","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1507\/endocrj.52.299","volume":"52","author":"D Dereli","year":"2005","unstructured":"Dereli, D., Dereli, T., Bayraktar, F., Ozgen, A. G. & Yilmaz, C. Endocrine and metabolic effects of rosiglitazone in non-obese women with polycystic ovary disease. Endocr. J. 52(3), 299\u2013308 (2005).","journal-title":"Endocr. J."},{"issue":"1","key":"85708_CR32","doi-asserted-by":"publisher","first-page":"35","DOI":"10.2131\/jts.27.35","volume":"27","author":"C Rothwell","year":"2002","unstructured":"Rothwell, C., McGuire, E. J., Altrogge, D. M., Masuda, H. & Iglesia, F. A. Chronic toxicity in monkeys with the thiazolidinedione antidiabetic agent troglitazone. J. Toxicol. Sci. 27(1), 35\u201347 (2002).","journal-title":"J. Toxicol. Sci."},{"key":"85708_CR33","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.matbio.2015.01.004","volume":"44\u201346","author":"S Duarte","year":"2015","unstructured":"Duarte, S., Baber, J., Fujii, T. & Coito, A. J. Matrix metalloproteinases in liver injury, repair and fibrosis. Matrix Biol. 44\u201346, 147\u2013156 (2015).","journal-title":"Matrix Biol."},{"key":"85708_CR34","doi-asserted-by":"publisher","first-page":"213","DOI":"10.3389\/fphys.2012.00213","volume":"3","author":"Y Saiman","year":"2012","unstructured":"Saiman, Y. & Friedman, S. L. The role of chemokines in acute liver injury. Front. Physiol. 3, 213 (2012).","journal-title":"Front. Physiol."},{"issue":"4","key":"85708_CR35","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1053\/j.gastro.2010.06.069","volume":"139","author":"F B\u00f6hm","year":"2010","unstructured":"B\u00f6hm, F. et al. FGF receptors 1 and 2 control chemically induced injury and compound detoxification in regenerating livers of mice. Gastroenterology 139(4), 1385\u20131396 (2010).","journal-title":"Gastroenterology"},{"issue":"1","key":"85708_CR36","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1146\/annurev-pharmtox-010715-103209","volume":"56","author":"S Rudraiah","year":"2016","unstructured":"Rudraiah, S., Zhang, X. & Wang, L. Nuclear receptors as therapeutic targets in liver disease: are we there yet?. Annu. Rev. Pharmacol. Toxicol. 56(1), 605\u2013626 (2016).","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"85708_CR37","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3389\/fphys.2012.00056","volume":"3","author":"HW Zimmermann","year":"2012","unstructured":"Zimmermann, H. W., Trautwein, C. & Tacke, F. Functional role of monocytes and macrophages for the inflammatory response in acute liver injury. Front. Physiol. 3, 56 (2012).","journal-title":"Front. Physiol."},{"issue":"1","key":"85708_CR38","doi-asserted-by":"publisher","first-page":"10713","DOI":"10.1038\/ncomms10713","volume":"7","author":"N Gomez-Ospina","year":"2016","unstructured":"Gomez-Ospina, N. et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat. Commun. 7(1), 10713 (2016).","journal-title":"Nat. Commun."},{"key":"85708_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/3453926","volume":"2016","author":"RN Jadeja","year":"2016","unstructured":"Jadeja, R. N., Upadhyay, K. K., Devkar, R. V. & Khurana, S. Naturally occurring Nrf2 activators: potential in treaent of liver injury. Oxid. Med. Cell. Longev. 2016, 1\u201313 (2016).","journal-title":"Oxid. Med. Cell. Longev."},{"issue":"4","key":"85708_CR40","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.clinre.2011.02.003","volume":"35","author":"S Z\u00fa\u00f1iga","year":"2011","unstructured":"Z\u00fa\u00f1iga, S., Firrincieli, D., Housset, C. & Chignard, N. Vitamin D and the vitamin D receptor in liver pathophysiology. Clin. Res. Hepatol. Gastroenterol. 35(4), 295\u2013302 (2011).","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"85708_CR41","doi-asserted-by":"publisher","first-page":"103296","DOI":"10.1016\/j.etap.2019.103296","volume":"74","author":"L Yu","year":"2020","unstructured":"Yu, L. et al. Integrating in vitro testing and physiologically-based pharmacokinetic (PBPK) modelling for chemical liver toxicity assessment: a case study of troglitazone. Environ. Toxicol. Pharmacol. 74, 103296 (2020).","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"85708_CR42","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1248\/bpb.b17-00913","volume":"41","author":"Y Yokoyama","year":"2018","unstructured":"Yokoyama, Y. et al. Comparison of drug metabolism and its related hepatotoxic effects in heparg, cryopreserved human hepatocytes, and HepG2 cell cultures. Biol. Pharm. Bull. 41, 722\u2013732 (2018).","journal-title":"Biol. Pharm. Bull."},{"key":"85708_CR43","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0009-2797(02)00054-6","volume":"142","author":"S Lloyd","year":"2002","unstructured":"Lloyd, S. et al. Differential in vitro hepatotoxicity of troglitazone and rosiglitazone among cryopreserved human hepatocytes from 37 donors. Chem. Biol. Interact. 142, 57\u201371 (2002).","journal-title":"Chem. Biol. Interact."},{"key":"85708_CR44","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1016\/j.tiv.2009.07.026","volume":"23","author":"Y Edling","year":"2009","unstructured":"Edling, Y., Sivertsson, L. K., Butura, A., Ingelman-Sundberg, M. & Ek, M. Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol. Vitr. 23, 1387\u20131395 (2009).","journal-title":"Toxicol. Vitr."},{"key":"85708_CR45","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1124\/dmd.111.038661","volume":"39","author":"T Usui","year":"2011","unstructured":"Usui, T., Hashizume, T., Katsumata, T., Yokoi, T. & Komuro, S. In vitro investigation of the glutathione transferase M1 and T1 null genotypes as risk factors for troglitazone-induced liver injury. Drug Metab. Dispos. 39, 1303\u20131310 (2011).","journal-title":"Drug Metab. Dispos."},{"issue":"1","key":"85708_CR46","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1093\/toxsci\/kfs326","volume":"132","author":"SR Khetani","year":"2013","unstructured":"Khetani, S. R. et al. Use of micropatterned cocultures to detect compounds that cause drug-induced liver injury in humans. Toxicol. Sci. Off. J. Soc. Toxicol. 132(1), 107\u2013117 (2013).","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"issue":"9","key":"85708_CR47","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1177\/1535370214531872","volume":"239","author":"SS Bale","year":"2014","unstructured":"Bale, S. S. et al. In vitro platforms for evaluating liver toxicity. Exp. Biol. Med. 239(9), 1180\u20131191 (2014).","journal-title":"Exp. Biol. Med."},{"key":"85708_CR48","doi-asserted-by":"publisher","unstructured":"Villeneuve, D. L. et al.. Adverse outcome pathway (AOP) development I: Strategies and principles. Toxicol. Sci. 142(2), 312\u2013320. https:\/\/doi.org\/10.1093\/toxsci\/kfu199 (2014).","DOI":"10.1093\/toxsci\/kfu199"},{"key":"85708_CR49","doi-asserted-by":"publisher","unstructured":"OECD. Guidance Document for the Use of Adverse Outcome Pathways in Developing Integrated Approaches to Testing and Assessment (IATA), OECD Series on Testing and Assessment, No. 260, OECD Publishing, Paris. https:\/\/doi.org\/10.1787\/44bb06c1-en (2017).","DOI":"10.1787\/44bb06c1-en"},{"key":"85708_CR50","doi-asserted-by":"publisher","first-page":"105557","DOI":"10.1016\/j.envint.2020.105557","volume":"137","author":"J Jeong","year":"2020","unstructured":"Jeong, J. & Choi, J. Development of AOP relevant to microplastics based on toxicity mechanisms of chemical additives using ToxCast and deep learning models combined approach. Environ. Int. 137, 105557 (2020).","journal-title":"Environ. Int."},{"key":"85708_CR51","doi-asserted-by":"publisher","first-page":"2849","DOI":"10.1007\/s00204-017-2002-1","volume":"91","author":"WR Proctor","year":"2017","unstructured":"Proctor, W. R. et al. Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury. Arch. Toxicol. 91, 2849\u20132863 (2017).","journal-title":"Arch. Toxicol."},{"issue":"4","key":"85708_CR52","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1053\/j.gastro.2020.06.010","volume":"159","author":"MN Bin Ramli","year":"2020","unstructured":"Bin Ramli, M. N. et al. Human pluripotent stem cell-derived organoids as models of liver disease. Gastroenterology 159(4), 1471\u20131486 (2020).","journal-title":"Gastroenterology"},{"key":"85708_CR53","doi-asserted-by":"publisher","unstructured":"EFSA Panel\u00a0on Contaminants in the Food Chain (EFSA CONTAM Panel), Risk to human health related to the presence of 2 perfluoroalkyl substances in food. EFSA J. https:\/\/doi.org\/10.2903\/j.efsa.2020.6223","DOI":"10.2903\/j.efsa.2020.6223"},{"issue":"7","key":"85708_CR54","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1289\/ehp.1307972","volume":"122","author":"AA Rooney","year":"2014","unstructured":"Rooney, A. A., Boyles, A. L., Wolfe, M. S., Bucher, J. R. & Thayer, K. A. Systematic review and evidence integration for literature-based environmental health science assessments. Environ. Health Perspect. 122(7), 711\u2013718 (2014).","journal-title":"Environ. Health Perspect."},{"issue":"4","key":"85708_CR55","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.jclinepi.2010.07.015","volume":"64","author":"H Balshem","year":"2011","unstructured":"Balshem, H. et al. GRADE guidelines: 3. Rating the quality of evidence. J. Clin. Epidemiol. 64(4), 401\u2013406 (2011).","journal-title":"J. Clin. Epidemiol."},{"issue":"4","key":"85708_CR56","doi-asserted-by":"publisher","first-page":"btw680","DOI":"10.1093\/bioinformatics\/btw680","volume":"33","author":"DL Filer","year":"2016","unstructured":"Filer, D. L., Kothiya, P., Setzer, R. W., Judson, R. S. & Martin, M. T. tcpl: the ToxCast pipeline for high-throughput screening data. Bioinformatics 33(4), btw680 (2016).","journal-title":"Bioinformatics"},{"key":"85708_CR57","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1124\/dmd.106.012633","volume":"35","author":"RS Obach","year":"2007","unstructured":"Obach, R. S., Walsky, R. L. & Venkatakrishnan, K. Mechanism-based inactivation of human cytochrome P450 enzymes and the prediction of drug-drug interactions. Drug Metab. Dispos. 35, 246\u2013255 (2007).","journal-title":"Drug Metab. Dispos."},{"key":"85708_CR58","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1093\/toxsci\/kfn109","volume":"105","author":"JJ Xu","year":"2008","unstructured":"Xu, J. J. et al. Cellular imaging predictions of clinical drug-induced liver injury. Toxicol. Sci. 105, 97\u2013105 (2008).","journal-title":"Toxicol. Sci."},{"key":"85708_CR59","unstructured":"US Food and Drug Administration, Application number 020720, S12, S14. (1999)."},{"key":"85708_CR60","unstructured":"US Food and Drug Administration, Medication Guide (Avandia). (2019)."},{"key":"85708_CR61","doi-asserted-by":"publisher","unstructured":"Tsaioun, K. et al.. Evidence-based methodology for identifying drugs with potential human liver toxicities using US EPA ToxCast data set (Version 6). Zenodo. https:\/\/doi.org\/10.5281\/zenodo.2529091 (2018).","DOI":"10.5281\/zenodo.2529091"},{"key":"85708_CR62","unstructured":"W. C. C. for I. D. monitoring Uppsala Monitoring Centre, \u201cGuideline for using VigiBase data in studies,\u201d 2018. Available: www.who-umc.org. (Accessed: 05 Feb 2021)."},{"issue":"6","key":"85708_CR63","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1002\/pds.677","volume":"10","author":"SJW Evans","year":"2001","unstructured":"Evans, S. J. W., Waller, P. C. & Davis, S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol. Drug Saf. 10(6), 483\u2013486 (2001).","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"85708_CR64","unstructured":"Tsaioun, K, et al. (2018, December 30). Evidence-based methodology for identifying drugs with potential human liver toxicities using WHO Vigibase data (Version 1). Zenodo. http:\/\/doi.org\/10.5281\/zenodo.2528922"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85708-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85708-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85708-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T00:45:33Z","timestamp":1670028333000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85708-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,18]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["85708"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-85708-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,18]]},"assertion":[{"value":"9 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6403"}}